Nancy Baker SILS Bioinformatics Seminar January 21, 2004 Presentation of Recent Trends in Computer-aided Drug Discovery By Alexander Tropsha Current Opinion in Drug Discovery & Development, 2000 Nancy Baker SILS Bioinformatics Seminar January 21, 2004

Terminology Overview “ics” : genetics, genomics, proteomics, bioinformatics, chemoinformatics Modifiers Structural Functional Pharmaco Informatics – general scientific discipline dealing with storage, analysis, and retrieval of information

Genetics Review DNA: TACGCTTCCGGATTCAA transcription RNA: AUGCGAAGGCCUAAGUU translation Amino Acids: PIRLMQTS Protein

Overview Continued – A simple example Protein Small molecule drug

Overview Continued – A simple example Protein Small molecule drug Protein Protein disabled … disease cured

Bioinformatics Chemoinformatics Protein Large databases Small molecule drug Large databases Large databases Tropsha compares these. Let’s look at some of the comparisons he makes. Mutual similarity techniques.

Size of databases Millions of entries in databases CAS : 23 million GeneBank : 5 million Total number of drugs worldwide: 60,000 Fewer than 500 characterized molecular targets Potential targets : 5,000-10,000

Lots of stuff – not much information. Some Numbers Millions of entries in databases CAS : 23 million GeneBank : 5 million Total number of drugs worldwide: 60,000 Fewer than 500 characterized molecular targets Potential targets : 5,000-10,000 Lots of stuff – not much information.

Bioinformatics Chemoinformatics Protein Large databases Small molecule drug Large databases Not all can be drugs Large databases Not all can be drug targets Tropsha compares these. Let’s look at some of the comparisons he makes. Mutual similarity techniques.

Bioinformatics Chemoinformatics Protein Large databases Small molecule drug Large databases Not all can be drugs Opportunity for data mining techniques Large databases Not all can be drug targets Opportunity for data mining techniques Tropsha compares these. Let’s look at some of the comparisons he makes. Mutual similarity techniques.

Trends in Chemoinformatics New methods need to establish QSAR for thousands of molecules Database mining and pharmacophore searching techniques Non-linear analytical methods applicable to large databases Design of new molecules with drug-like properties rather than mere high-affinity ligands for existing targets.

Trends in Bioinformatics Traditional: sequence to function New thought: structure to function. (Same structure – different sequences; Structure more conserved than sequence.)

Vision: Integration of Chemoinformatics and Bioinformatics CADD: computer-aided drug discovery (instead of computer-aided drug design) “Start with a gene sequence and using computational procedures design a molecule capable of affecting the activity of this gene or its product”

Questions? Once a scientist find thousands of potentially interacting molecules/proteins … then what? Proof of concept?